TolC facilitates the intracellular survival and immunomodulation of salmonella typhi in human Host cells.

Introduction : Salmonella enterica serovar Typhi ( S . Typhi) causes typhoid fever, a systemic infection that affects millions of people worldwide. S . Typhi can invade and survive within host cells, such as intestinal epithelial cells and macrophages, by modulating their immune responses. However, the immunomodulatory capability of S . Typhi in relation to TolC-facilitated efflux pump function remains unclear. Methods : The role of TolC, an outer membrane protein that facilitates efflux pump function, in the invasion and immunomodulation of S . Typhi, was studied in human intestinal epithelial cells and macrophages. The tolC deletion mutant of S . Typhi was compared with the wild-type and its complemented strain in terms of their ability to invade epithelial cells, survive and induce cytotoxicity in macrophages, and elicit proinflammatory cytokine production in macrophages. Results : The tolC mutant, which has a defective outer membrane, was impaired in invading epithelial cells compared to the wild-type strain, but the intracellular presence of the tolC mutant exhibited greater cytotoxicity and induced higher levels of proinflammatory cytokines ( IL-1β and IL-8 ) in macrophages compared to the wild-type strain. These effects were reversed by complementing the tolC mutant with a functional tolC gene. Discussion : Our results suggest that TolC plays a role in S . Typhi to efficiently invade epithelial cells and suppress host immune responses during infection. TolC may be a potential target for the development of novel therapeutics against typhoid fever.